Project summary Ischemic heart disease (IHD) is a major cause of morbidity and mortality in the US. Cell-based therapies have recently emerged as a promising alternative to existing pharmacological and surgical procedures for augmentation of cardiac structure and function. Success of animal studies and preclinical models of cell therapy have provided the basis for clinical testing of different stem cell types in heart failure patients. Although, stem cell administration has largely resulted in better prognosis in patients yet functional gains remain incremental. The adoptively transferred stem cells are hampered in their ability to survive, engraft and proliferate in the ischemic myocardium environment. Moreover, a critical need is felt to understand interaction of the transplanted stem cells with the ischemic cardiac environment. The injured myocardium secretes factors that recruit and mobilize immune cells to the site of injury involved in removing dead tissue and scar formation as part of the cardiac inflammatory/immune response. Transplanted stem cells are exposed to pro-inflammatory factors and activated immune cells but their effect remains unknown. The fundamental question is whether cardiac inflammatory/immune response is a determinant of stem cell mediated cardiac repair. We have recently identified cortical bone derived stem cells (CBSCs) from the bone stroma and their administration in the heart enhances function after myocardial damage. Our preliminary findings show that CBSCs possess properties of survival and proliferation compared to other known stem cell types. Importantly, CBSCs salutary effects are tied to secretion of paracrine factors that modulate cardiac immune response after injury. Therefore, we hypothesize that CBSCs paracrine factors transform cardiac immune cells into a pro-reparative state enhancing their contribution towards myocardial repair response after injury. Our goal is to understand the interaction of transplanted CBSCs and cardiac immune response and determine its consequence for repair in the heart following injury. We will extend these studies to develop a therapeutic strategy for delivery of CBSCs paracrine factors to promote cardiac repair response after myocardial damage. CBSCs paracrine modulators represent a new direction to enhance cardiac structure and function in after ischemic injury.